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PMID: 18436956 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Structural effects of Parkinson's disease linked DJ-1 mutations.

Protein science : a publication of the Protein Society ·Vol. 17 ·No. 5 ·2008-05-00 ·Pages 855-68

Malgieri G, Eliezer D

Abstract

Mutations in the protein DJ-1 are associated with familial forms of Parkinson's disease, indicating that DJ-1 may be involved in pathways related to the etiology of this disorder. Here we have used solution state NMR and circular dichroism spectroscopies to evaluate the extent of structural perturbations associated with five different Parkinson's disease linked DJ-1mutations: L166P, E64D, M26I, A104T, and D149A. Comparison of the data with those obtained for the wild-type protein shows that the L166P mutation leads to severe and global destabilization and unfolding of the protein structure, while the structure of the E64D mutation, as expected, is nearly unperturbed. Interestingly, the remaining three mutants all show different degrees of structural perturbation, which are accompanied by a reduction in the thermodynamic stability of the protein. The observed structural and thermodynamic differences are likely to underlie any functional variations between these mutants and the wild type, which in turn are likely responsible for the pathogenicity of these mutations.

MeSH Terms
Amino Acid Sequence Circular Dichroism Crystallography, X-Ray Humans Intracellular Signaling Peptides and Proteins/chemistry,genetics Molecular Sequence Data Mutation Nuclear Magnetic Resonance, Biomolecular Oncogene Proteins/chemistry,genetics Parkinson Disease/genetics Protein Deglycase DJ-1 Protein Folding Protein Structure, Secondary Solutions
Chemicals
Intracellular Signaling Peptides and Proteins Oncogene Proteins Solutions PARK7 protein, human Protein Deglycase DJ-1
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Malgieri Gaetano
Department of Biochemistry and Program in Structural Biology, Weill Cornell Medical College, New York, New York 10021, USA.
Eliezer David
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Article Info
Journal
Protein science : a publication of the Protein Society
Abbr.
Protein Sci
ISSN
1469-896X
DOI
10.1110/ps.073411608
Published
2008-05-00
Pages
855-68
Language
English
Region
United States
NLM ID
9211750
PMCID
PMC2327288
Subset
IM
Grants
NIA NIH HHS · R01 AG019391 · United States
NIGMS NIH HHS · P41 GM66354 · United States
NIA NIH HHS · R37 AG019391 · United States
NIA NIH HHS · R01 AG019391-08 · United States
NIA NIH HHS · R01 AG025440 · United States
NIA NIH HHS · R01 AG025440-03 · United States
NIGMS NIH HHS · P41 GM066354 · United States
External Links
PubMed source DOI: 10.1110/ps.073411608 PMC Full Text View journal details
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